Viscous formulations and their use in needle-free injection

ABSTRACT

Formulations are described that are viscous and will benefit from needle-free delivery at high driving pressures. Conventional delivery of these viscous formulations by hypodermic syringes is inconvenient as well as painful. Formulations include those which have a viscosity of about 5 cS or more at about 20° C. and which can have 0.5 ml or more administered by a needle-free injector in about 0.1 second±0.02 seconds.

CROSS-REFERENCE

This application is a continuation-in-part application of InternationalApplication Serial No. PCT/ US2006/044778 filed Nov. 16, 2006, whichapplication claims priority to Provisional Application Ser. No.60/738,089 filed Nov. 17, 2005, which are incorporated herein byreference in their entirety noting that the current application controlsto the extent there is any contradiction with any earlier applicationsand to which applications we claim priority under 35 USC §119 and 120.

FIELD OF THE INVENTION

The present invention relates to various classes of viscous formulationsand the delivery via needle-free injection for parenteral and otherpharmaceutical applications.

BACKGROUND OF THE INVENTION

Modern drug development has shown that the market for injectable drugsis growing, since the majority of these molecules are too large andfragile to be delivered by other methods such as orally. However, it isdifficult to formulate many of these molecules into stable solutionsthat are sufficiently concentrated to inject an efficacious amount in areasonable sized dose (<1 ml). As a result, the formulation may be quiteviscous, often up to 10,000 times thicker than water i.e. 10,000 cS(centistokes) or higher. Also, the advent of controlled releasestrategies has opened new areas for development and delivery offormulations. For parenteral applications, the viscosity of enhancedformulations has been an issue with several controlled releaseformulations. Liquids with viscosities significantly higher than waterbecome increasingly difficult, if not impractical, to inject asviscosity increases using a conventional needle and syringe.

Viscous formulations containing polymers, for example, are employed forthe controlled release of drugs after Intra-venous (IV) subcutaneous(SC), intra-dermal (ID) or intra-muscular (IM) injection. Theseformulations are notoriously difficult to inject, requiring a largeforce to be delivered by the hand of the care-giver, and often quitepainful for the patient. The force required for injection is associatedwith viscous drag of the formulation while traversing the length of theneedle. Consequently, large bore needles are employed (creating evengreater levels of pain), but still the injection time can be in theorder of minutes or more.

The ability to inject a drug incorporated into a polymer to a localizedsite and have the polymer form a semi-solid drug depot has a number ofadvantages. Among these advantages is ease of application localizeddelivery, prolonged drug delivery, and better compliance with prescribedtherapy due to less frequent dosing. The better compliance is veryimportant for delivery of psychiatric drugs, wherein the disease statecan make compliance difficult or impossible, and a depot can allow forinfrequent, e.g. monthly, dosing in a clinical setting. For thesereasons a large number of in situ setting polymeric delivery systemshave been developed and investigated for use in delivering a widevariety of drugs.

Currently, there are few synthetic or natural polymeric materials whichcan be used for the controlled delivery of drugs, including peptide andprotein drugs, because of the strict regulatory compliance requirements,such as biocompatibility, clearly defined degradation pathway, andsafety of the degradation products. The most widely investigated andadvanced biodegradable polymers in regard to available toxicological andclinical data are the aliphatic poly(.alpha.-hydroxy acids), such aspoly(D,L- or L-lactic acid) (PLA) and poly(glycolic acid) (PGA) andtheir copolymers (PLGA). These polymers are commercially available andare presently being used in medical products, for example asbioresorbable sutures. An FDA-approved system for controlled release ofleuprolide acetate, the Lupron Depot™, is also based on PLGA copolymers.The Lupron Depot consists of injectable microspheres, which releaseleuprolide acetate over a prolonged period (e.g., about days) for thetreatment of prostate cancer.

A. S. Sawhney and J. A. Hubbell, J. Biomed. Mat. Res., 24, 1197-1411(1990), synthesized terpolymers of D,L-lactide, glycolide andc-caprolactone which degrade rapidly in vitro. The hydrophilicity of thematerial was increased by copolymerization with a poloxamer surfactant(Pluronic F-68). This poloxamer is a block copolymer comprising about80% by weight of a relatively hydrophobic poly(oxypropylene) block and20% by weight of a hydrophilic poly(oxyethylene) block. Copolymerizationwith the poloxamer resulted in a stronger and partly crystallinematerial which was mechanically stable at physiological temperatures(e.g. 37.degree. C.) in water.

One system, which can be fabricated in aqueous solution, is a class ofblock copolymers referenced above and marketed under the Pluronic™tradename. These copolymers are composed of two different polymerblocks, i.e. hydrophilic poly(oxyethylene) blocks and hydrophobicpoly(oxypropylene) blocks to make up a triblock ofpoly(oxyethylene)-poly(oxypropylene)-poly(oxyethylene). The triblockcopolymers absorb water to form gels which exhibit reverse thermalgelation behavior.

Churchill et al, U.S. Pat. Nos. 4,526,938 and 4,745,160 show copolymersthat are either self-dispersible or can be made self-dispersible inaqueous solutions. These copolymers are ABA triblock or AB blockcopolymers composed of hydrophobic A-blocks, such as polylactide (PLA)or poly(lactide-co-glycolide) (PLGA), and hydrophilic B-blocks, such aspolyethylene glycol (PEG) or polyvinyl pyrrolidone.

Dunn et al, in U.S. Pat. No. 5,324,519, disclose the composition of aliquid formulation of a thermoplastic polymer and a pharmaceuticallyacceptable organic solvent (trade name Atrigel). The composition isadministered as a liquid to an implant site, whereupon the solventdiffuses or dissipates into the surrounding aqueous tissue fluids. Thethermoplastic polymer is not soluble in these aqueous fluids so that itcoagulates or solidifies to form a microporous solid or gelatinousmatrix. The composition is a liquid formulation of a thermosetprepolymer or copolymer, preferably an acrylic ester-terminatedbiodegradable prepolymer, which is capable of cross-linking in situ toform a polymeric or copolymeric solid or gelatinous matrix.

In U.S. Pat. No. 6,117,949, Rathi et al. disclose A water solublebiodegradable ABA- or BAB-type triblock polymer is disclosed that ismade up of a major amount of a hydrophobic polymer made of apoly(lactide-co-glycolide) copolymer or poly(lactide) polymer as theA-blocks and a minor amount of a hydrophilic polyethylene glycol polymerB-block, that possesses reverse thermal gelation properties.

U.S. Pat. No. 5,980, 948 describes a composition comprised of a productincluding a biologically active agent encapsulated in a matrixcomprising a polyetherester copolymer, such as a polyethylene glycolterephthalate/polybutylene terephthalate copolymer. The polyetherestercopolymer protects the biologically active agent (including proteins,peptides, and small drug molecules) from degradation or denaturation.

U.S. Pat. No. 5,747,058 describes a delivery system in situ which usessucrose acetate isobutyrate (SAIB). Sucrose acetate isobutyrate is ahighly lipophilic sugar derivative, which is currently used asstabiliser and emulsifying agent to human diets in the Food Industry.This technology, called SABER™, was patented by Tipton and Richard(Southern Biosystems, Inc.) in 1995. The high viscosity of the liquidsucrose acetate isobutyrate carrier is lowered by the addition of awater soluble or miscible solvent such as ethanol or dimethylsulfoxide.After addition of the drug, the composition is injected and forms ahighly viscous implant in situ, which releases the drug over time.

EP 1184032 describes a method for producing hydrogels, based oncrystallization of dextran or derivatives thereof. These hydrogels finduse in pharmaceutical, medical and biotechnological applications, e.g.as controlled release systems for the delivery of active ingredients inin vivo and in vitro applications. The hydrogels according to thepresent invention are priced by crystallization from an aqueous solutionthat is essentially free of organic solvents or crystallizationenhancers.

EP0842657 describes a two phase controlled release system containingdextran and polyethylene glycol. EP0941068 describes a two phase dextrancontaining controlled release system for proteins.

Many of these and other controlled release formulations are limited bytheir elevated viscosity, which leads to many delivery difficulties,such as high required hand strength, long delivery times, and pain andfear associated with the large bore needle. Thus, there is a need todeliver these compounds in a rapid, automated fashion without a needle.

Needle-free injectors are available using many different types ofenergy, and the energy may be supplied by the user, for example where aspring is manually compressed and latched to temporarily store theenergy until it is required to “fire” the injector. Alternatively, theinjector may be supplied having the energy already stored—for instanceby means of a precompressed spring (mechanical or gas), or pyrotechniccharge.

Some injectors are intended for disposal after a single use, whereasothers have a re-loadable energy storage means and a disposablemedicament cartridge, and there are many combinations to suit particularapplications and markets. For the purposes of the present disclosure,the term “actuator” will be used to describe the energy storage andrelease mechanism, whether or not it is combined with the medicamentcartridge. In all cases, it is necessary to arrange for sufficient forceat the end of the piston stroke to deliver the entire medicament at therequired pressure.

EP 0 063 341 and EP 0 063 342 disclose a needle-free injector whichincludes a piston pump for expelling the liquid to be injected, which isdriven by a motor by means of a pressure agent. The liquid container ismounted laterally to the piston pump. The amount of liquid required foran injection is sucked into the pump chamber by way of an inlet passageand a flap check valve when the piston is retracted. As soon as thepiston is moved in the direction of the nozzle body the liquid is urgedthrough the outlet passage to the nozzle and expelled. The piston of thepiston pump is a solid round piston.

EP 0 133 471 describes a needle-free vaccination unit which is operatedwith carbon dioxide under pressure, from a siphon cartridge by way of aspecial valve.

EP 0 347 190 discloses a vacuum compressed gas injector in which thedepth of penetration of the injected drug can be adjusted by means ofthe gas pressure and the volume of the drug can be adjusted by way ofthe piston stroke.

EP 0 427 457 discloses a needle-free hypodermic syringe which isoperated by means of compressed gas by way of a two-stage valve. Theinjection agent is disposed in an ampoule which is fitted into aprotective casing secured to the injector housing. The ampoule is fittedon to the end of the piston rod. Disposed at the other end of theampoule is the nozzle whose diameter decreases towards the end of theampoule.

WO 89/08469 discloses a needle-free injector for one-off use. WO92/08508 sets forth a needle-free injector which is designed for threeinjections. The ampoule containing the drug is screwed into one end ofthe drive unit, with the piston rod being fitted into the open end ofthe ampoule. At its one end, the ampoule contains the nozzle throughwhich the drug is expelled. A displaceable closure plug is providedapproximately at the center of the length of the ampoule. The dose to beinjected can be adjusted by changing the depth of the ampoule. Thepiston rod which projects from the drive unit after actuation of theinjector is pushed back by hand. Both units are operated with compressedgas.

WO 93/03779 discloses a needle-free injector with a two-part housing anda liquid container which is fitted laterally to the unit. The drivespring for the piston is stressed by means of a drive motor. The springis released as soon as the two parts of the housing are displacedrelative to each other by pressing the nozzle against the injectionlocation. Respective valves are provided in the intake passage for theliquid and in the outlet of the metering chamber.

WO 95/03844 discloses a further needle-free injector. It includes aliquid-filled cartridge which at one end includes a nozzle through whichthe liquid is expelled. At the other end the cartridge is closed by acap-type piston which can be pushed into the cartridge. A piston whichis loaded by a pre-stressed spring, after release of the spring,displaces the cap-type piston into the cartridge by a predetermineddistance, with the amount of liquid to be injected being expelled inthat case. The spring is triggered as soon as the nozzle is pressedsufficiently firmly against the injection location. This injector isintended for one-off or repeated use. The cartridge is arranged in frontof the spring-loaded piston and is a fixed component of the injector.The position of the piston of the injector which is intended for aplurality of uses is displaced after each use by a distance in adirection towards the nozzle. The piston and the drive spring cannot bereset. The pre stressing of the spring is initially sufficiently greatto expel the entire amount of liquid in the cartridge all at once. Thespring can only be stressed again if the injector is dismantled and thedrive portion of the injector assembled with a fresh, completely filledcartridge.

U.S. Pat. No. 5,891,086 describes a needle-free injector, combining anactuator and a medicament cartridge. The cartridge is pre-filled with aliquid to be injected in a subject, and having a liquid outlet and afree piston in contact with the liquid, the actuator comprising animpact member urged by a spring and temporarily restrained by a latchmeans, the impact member being movable in a first direction under theforce of the spring to first strike the free piston and then to continueto move the piston in the first direction to expel a dose of liquidthrough the liquid outlet, the spring providing a built-in energy storeand being adapted to move from a higher energy state to a lower energystate, but not vice versa. The actuator may comprise trigger means tooperate the said latch, and thus initiate the injection, only when apredetermined contact force is achieved between the liquid outlet of thesaid cartridge and the subject. Further examples and improvements tothis needle-free injector are found in U.S. Pat. No. 6,620,135, U.S.Pat. No. 6,554,818, U.S. Pat. No. 6,415,631, U.S. Pat. No. 6,409,032,U.S. Pat. No. 6,280,410, U.S. Pat. No. 6,258,059, U.S. Pat. No.6,251,091, U.S. Pat. No. 6,216,493, U.S. Pat. No. 6,179,583, U.S. Pat.No. 6,174,304, U.S. Pat. No. 6,149,625, U.S. Pat. No. 6,135,979, U.S.Pat. No. 5,957,886, U.S. Pat. No. 5,891,086, and U.S. Pat. No.5,480,381, incorporated herein by reference.

U.S. Pat. No. 3,859,996, Mizzy, discloses a controlled leak method toensure that the injector orifice is placed correctly at the requiredpressure on the subject's skin at the correct normal to the skinattitude. When placement conditions are met, controlled leak is sealedoff by contact pressure on the subject's skin, the pressure within theinjector control circuit rises until a pressure sensitive pilot valveopens to admit high pressure gas to drive the piston and inject themedicament.

WO Patent 82/02835. Cohen and Ep-A-347190, Finger, discloses a method toimprove the seal between the orifice and the skin and prevent relativemovement between each. This method is to employ a vacuum device to suckthe epidermis directly and firmly onto the discharge orifice. Thedischarge orifice is positioned normal to the skin surface in order tosuck the epidermis into the orifice. This method for injection of themedicament into the skin and the injector mechanism are different and donot apply to the present invention because of its unique ampule design.

U.S. Pat. No. 3,859,996, Mizzy, discloses a pressure sensitive sleeve onthe injector which is placed on the subject, whereby operation of theinjector is prevented from operating until the correct contact pressurebetween orifice and the skin is achieved. The basic aim is to stretchthe epidermis over the discharge orifice and apply the pressurizedmedicament at a rate which is higher than the epidermis will deform awayfrom the orifice.

U.S. Pat. No. 5,480,381, T. Weston, discloses a means of pressuring themedicament at a sufficiently high rate to pierce the epidermis before ithas time to deform away from the orifice. In addition, the devicedirectly senses that the pressure of the discharge orifice on thesubject's epidermis is at a predetermined value to permit operation ofthe injector. The device is based on a cam and cam follower mechanismfor mechanical sequencing, and contains a chamber provided with a liquidoutlet for expelling the liquid, and an impact member, to dispell theliquid.

U.S. Pat. No. 5,891,086, T. Weston, describes a needle-free injectorthat contains a chamber that is pre-filled with a pressurized gas whichexerts a constant force on an impact member in order to strikecomponents of a cartridge and expulse a dose of medicament. This devicecontains an adjustment knob which sets the dose and the impact gap, anduses direct contact pressure sensing to initiate the injection.

A number of biologically-active agents in viscous formulations wouldbenefit from being delivered using the needle-free injector. This groupcould consist of (but not limited to) anti-inflammatory agents,antibacterial agents, antiparasitic agents, antifungal agents, antiviralagents, anti-neoplastic agents, analgesic agents, anaesthetics,vaccines, central nervous system agents, growth factors, hormones,antihistamines, osteoinductive agents, cardiovascular agents, anti-ulceragents, bronchodilators, vasodilators, birth control agents andfertility enhancing agents, interferon alpha, growth hormone,osteoporosis drugs including PTH and PTH analogs and fragments, obesitydrugs, psychiatric drugs, anti-diabetes, female infertility, AIDS,treatment of growth retardation in children, hepatitis, multiplesclerosis, migraine headaches, and allergic reactions.

SUMMARY OF THE INVENTION

The invention includes a device for the delivery of an activepharmaceutical ingredient which device is comprised of a needle-freeinjector comprised of a channel and one exit opening. The ratio of thechannel length to the channel exit opening diameter is less than 10. Thedevice is filled with a formulation which has viscosity of 5 cS or moreat 20° C. and the formulation is comprised of a pharmaceutically activedrug and a pharmaceutically acceptable carrier. In some embodiments theratio of the length to the exit diameter is less than 7 and theviscosity of the formulation is 10 cS or more at 20° C.

The invention also includes a method of dispensing a formulation whichincludes loading a formulation into a needle-free delivery devicecomprising a channel and an exit opening with a channel length to exitopening diameter ratio of less than 10 where the formulation iscomprised of a pharmaceutically active drug in a carrier and has aviscosity of 5 cS or more at 20° C. The loaded formulation is thenextruded through the exit opening at a rate of 500 microliters or moreper second and the rate may be 5,000 microliters or more per second.

The device of the present invention comprises an actuator for use inconjunction with a cartridge to form a needle-free injector, thecartridge being pre-filled with a liquid to be injected in a subject,the cartridge having a liquid outlet and a free piston inward of theliquid outlet in contact with the liquid, said actuator comprising:

(a) a housing having a forward portion adapted to be connected with thecartridge;

(b) impact member mounted within said housing inward of the forwardportion so as to be movable from a first position toward the forwardportion to strike the free piston when a cartridge is connected and tocontinue to move the free piston toward the liquid outlet whereby a doseof the liquid is expelled through the liquid outlet in the cartridge;

(c) a chamber within said housing pre-filled with pressurized gas andconnected with said impact member such that said pressurized gas isconstantly in communication with and constantly exerts a force on saidimpact member to normally urge said impact member toward the liquidoutlet; and

(d) a latch within said housing which engages said impact member toprevent movement of the impact member toward the forward portion inresponse to said force exerted by said pressurized gas, and beingmounted to be movable out of engagement with said impact member to afiring position, in which said latch permits such movement.

In one formulation that would especially benefit from needle-freedelivery, the biologically active agent is psychiatric drug, preferablyan anti-psychotic drug for treatment of conditions such as schizophreniaor mania associated with bipolar disorder. Injectable, sustained releaseformulations of these compounds would lead to a great improvement inoutcomes, as the subjects cannot reliably self medicate or present at aphysicians office. Many compounds could be used with the presentinvention for the treatment of psychoses, including but not limited toAripiprazole, Clozapine, Zyprasidone, Molindone, Quetiapine, Olanzapine,Risperidone, Paliperidone, Iloperidone, and pharmaceutically acceptablesalts and ester forms thereof.

Risperidone has been previously delivered in a sustained release form,as described in patents U.S. Pat. No. 5,688,801, U.S. Pat. No.5,770,231, U.S. Pat. No. 5,792,477, U.S. Pat. No. 5,916,598, U.S. Pat.No. 5,965,168, U.S. Pat. No. 6,110,503, U.S. Pat. No. 6,110,921, U.S.Pat. No. 6,194,006, U.S. Pat. No. 6,264,987, U.S. Pat. No. 6,368,632,U.S. Pat. No. 6,379,703, U.S. Pat. No. 6,379,704, U.S. Pat. No.6,403,114, U.S. Pat. No. 6,534,092, and U.S. Pat. No. 6,596,316. Thesepatents disclose a sustained release microparticle formulation of theRisperidone. Many improvements over this art is possible, including lessfrequent dosing, smaller injection volumes, no needle vs a fairly large,20 gauge needle, immediate onset of action that does not require an oral3 week loading dose, Extended stability with no requirement forreconstitution.

The requirement for a fairly large needle, 20 gauge or larger for thedelivery of viscous formulations with a need and syringe, can beespecially significant. Large needles can be very painful. They can alsobe visually intimidating, especially in patients ungoing psychoticepisodes. Because of these issues, often the preferred needle is smallerthan would otherwise be used, leading to long delivery times, and therequirement of significant hand strength on the part of the care giver.This often rules out the possibility of treatment in a home setting,either self treatment or by an relatively un-trained care giver such asa family member. The inability to dose at home leads to higher costs oftherapy and lower compliance.

An aspect of the invention is a desirable delivery time of highviscosity formulations via needleless injection.

Another aspect of the invention is acceptable pain associated withinjection of high viscosity formulations.

Another aspect of the invention relates to fear of needles associatedwith injection of high viscosity formulations.

Another aspect of the invention relates to the danger of needle stickinjury and cross-contamination associated with injection of highviscosity formulations.

Another aspect of the invention relates to the preparation associatedwith injection of high viscosity formulations, by supplying apre-filled, single use disposable injector.

Another aspect of the invention relates to the drug release profileassociated with injection of high viscosity depot formulation,especially surface eroding systems.

These and other aspects of the invention will become apparent to thosepersons skilled in the art upon reading the details of the devices andmethodology as more fully described below.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention is best understood from the following detailed descriptionwhen read in conjunction with the accompanying drawings. It isemphasized that, according to common practice, the various features ofthe drawings are not to-scale. On the contrary, the dimensions of thevarious features are arbitrarily expanded or reduced for clarity.Included in the drawings are the following figures:

FIG. 1 is an image showing the dimensions of hole length and criticallength (typically diameter) for the exit opening of the nozzle of theneedle-free injector in this figure, the ratio of hole length todiameter is in a range of 1.5 to 1.7±20%. At that ratio, for viscositiesless than ˜10,000 cS, viscous losses are negligible.

FIG. 2 is a graph showing the effect of viscosity on injection time fora needle with length to diameter ratio of 22.2 (white) versusNeedle-free with a length to diameter ratio of 2.3 (black) delivery.Both methods delivered 0.5 mL of non-thixotropic fluid. Needleinjections were using 23 G needle, with maximum hand force that could beapplied by tester (approx. 20 N/5 lbF).

FIG. 3 is a graph showing the injection times of a needle & syringeagainst the needle-free injector; both axes are using logarithmicscales.

DETAILED DESCRIPTION OF THE INVENTION

Before the present devices, formulations and methods are described, itis to be understood that this invention is not limited to particularembodiments described, as such may, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only, and is not intended to belimiting, since the scope of the present invention will be limited onlyby the appended claims.

Where a range of values is provided, it is understood that eachintervening value, to the tenth of the unit of the lower limit unlessthe context clearly dictates otherwise, between the upper and lowerlimits of that range is also specifically disclosed. Each smaller rangebetween any stated value or intervening value in a stated range and anyother stated or intervening value in that stated range is encompassedwithin the invention. The upper and lower limits of these smaller rangesmay independently be included or excluded in the range, and each rangewhere either, neither or both limits are included in the smaller rangesis also encompassed within the invention, subject to any specificallyexcluded limit in the stated range. Where the stated range includes oneor both of the limits, ranges excluding either or both of those includedlimits are also included in the invention.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods andmaterials similar or equivalent to those described herein can be used inthe practice or testing of the present invention, some potential andpreferred methods and materials are now described. All publicationsmentioned herein are incorporated herein by reference to disclose anddescribe the methods and/or materials in connection with which thepublications are cited. It is understood that the present disclosuresupercedes any disclosure of an incorporated publication to the extentthere is a contradiction.

It must be noted that as used herein and in the appended claims, thesingular forms “a”, “an”, and “the” include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to “aformulation” includes a plurality of such formulations and reference to“the polymer” includes reference to one or more polymers and equivalentsthereof known to those skilled in the art, and so forth.

The publications discussed herein are provided solely for theirdisclosure prior to the filing date of the present application. Nothingherein is to be construed as an admission that the present invention isnot entitled to antedate such publication by virtue of prior invention.Further, the dates of publication provided may be different from theactual publication dates which may need to be independently confirmed.

DEFINITIONS

Specific gravity: ratio of a compound's density to that of water.

Centipoise and centistokes: different measurements of viscosity, notjust different units. Centipoise is a dynamic measurement of viscositywhereas centistoke is a kinematic measurement of viscosity. Theconversion from centistoke and centipoise to s.i. units is given below:

1 cS=0.0001 m²/s 1 cP=0.001 Ns/m²

Conversion from centistoke to centipoise:

centipoise=centistoke×density of liquid

Formulation shall mean any liquid, solid, or other state of matter thatcan be injected. Preferred formulations are liquid formulations,including polymers and gels. Formulations include but are not limited tothose containing excipients that are suitable for injection, and containone or more active pharmaceutical ingredients. Aspects of the inventionare generally apparent when using formulations with viscositiessufficiently high that the formulation can not administered by injectionwithout significant problems.

A depot injection is an injection, usually subcutaneous, intravenous, orintramuscular, of a pharmacological agent which releases its activecompound in a consistent way over a long period of time. Depotinjections may be available as certain forms of a drug, such asdecanoate salts or esters. Examples of depot injections include DepoProvera and haloperidol decanoate. Depots can be, but are not always,localized in one spot in the body.

Bulk erosion: The rate of water penetration into the depot exceeds therate at which the depot is eroded (i.e. transformed into water solubleproducts)—leading to an erosion process that occurs throughout theentire volume of the depot—true with most hydrophilic polymers used indrug delivery currently.

Surface Erosion: The rate of water penetration into the depot is slowerthan the rate at which the depot is eroded—The depot starts erodingbefore water has penetrated the entire volume of the device.

“Biodegradable” means that the depot can chemically break down ordegrade within the body to form nontoxic components. The rate ofdegradation can be the same or different from the rate of drug release.

s.i. units: international system of units

API: Active Pharmaceutical Ingredient or drug

TABLE 1 Examples of peptide/protein controlled, release systems based onPLGA. Drug Trade name Company Polymer Route Application buserelinProfact ®Depot, Hoechst Marion PLGA s/c implant Prostate cancer acetateSuprefact ®Depot Roussel goserelin Zoladex Depot Astra Zeneca PLGA s/cimplant Prostate cancer, acetate endometrioses leuprorelinLupron ®Depot, Takeda- PLGA 3-month depot Prostate cancer, acetateEnantone ®Depot, Abbott PLA suspension, endometrioses Enantone ®GynDepot 1-month suspension Trenantone ® 3-month suspension octreotideSandostatin Novartis PLGA s/c suspension GH suppression, acetateLAR ®Depot Pharma anti cancer triptorelin Decapeptyl ® Debiopharma PLGAs/c depot LHRH agonist, Depot injection prostate cancer recombinantNutropin ®Depot, Genentech- PLGA monthly s/c Growth hormone human growth[discontinued Alkermes injection deficiency hormone commercialisationsince June 2004]

Centipoise and centistokes are different measurements of viscosity, notjust different units. Centipoise is a dynamic measurement of viscositywhereas centistoke is a kinematic measurement of viscosity. Theconversion from centistoke and centipoise to s.i. units is given below:

1 cS=0.0001 m2/s 1 cP=0.001 Ns/m2

INVENTION IN GENERAL

The invention includes needle-free injector devices which devices areloaded with containers which containers include high viscosityformulations comprised of pharmaceutically active drug wherein the highviscosity formulation is difficult to inject using a hypodermicneedle-free injector device. As shown within FIG. 3 a needle-freeinjector device of the invention can include formulations which haveviscosities over a relatively wide range such as from 1 cS to 10,000 cSor more at about 20° C. and still deliver about 0.5 ml of formulation inless than about 1 second. This is obtained by utilizing a needle-freeinjector device with a nozzle having an opening and a length such that arange of volumes such as from 0.05 mL to 1.5 mL or more of formulationhaving the viscosity in the range of 1 cS to about 10,000 cS can bedelivered out of the needle-free injector device through the nozzle andinto the patient in about 1 second or less, more preferably less thanabout 0.1 second.

Another aspect of the invention is to employ a nozzle configuration in aneedle-free injector that has a substantially larger orifice/lengthratio than a needle, making it is possible to substantially reduce oreliminate the effects of viscous drag resulting from fully developedlaminar flow and therefore safely, conveniently, and reproduciblydeliver the injectate independent of formulation viscosity.

An aspect of the invention is to minimize the impact of viscocity onsuch delivery parameters as delivery time, rate of delivery, velocity ofdelivered medicament, penetration depth, and reproducibility ofdelivery. An aspect of the invention of obtaining delivery of highviscosity formulations is to use a needle-free injection constructed toallow for minimizing the ratio of orifice length to orifice exitdiameter. This ratio may be less than 10, less than 7, less than 5, orabout 2±20% or ±10% or ±5% for all ratios.

It is an aspect of the invention to deliver relatively viscousformulations for their sustained release (Depot) properties to patientssuffering from disease states with treatments that benefit from asustained release profile. Examples include compounds that requirechronic injections, including but not limited to peptide and proteindrugs. The use of sustained release formulation has the advantage ofrequiring fewer injections, leading to less pain, higher compliance, andless needle phobia.

One disease state that benefits greatly from sustained release, depotformulations is psychoses, including but not limited to schizophreniaand bi-polar disorder, including mania associated with bi-polardisorder.

Because psychotic states often lead to limited- or non-compliance withprescribed therapies, almost all anti-psychotic drugs benefit from adepot formulation. Examples of anti-psychotic drugs that benefit fromthe present invention include, but are not limited to Chlorpromazine,Fluphenazine, Mesoridazine, Perphenazine, Prochlorperazine, Promazine,Thioridazine/Sulforidazine, Trifluoperazine, Indoles (Molindone),Butyrophenones (Azaperone, Benperidol, Droperidol, Haloperidol),Thioxanthenes (Flupentixol, Chlorprothixene, Thiothixene,Zuclopenthixol), diphenylbutylpiperidines (Fluspirilene, Penfluridol,Pimozide), Loxapine) Butyrophenones (Melperone), Indoles (Sertindole,Ziprasidone), Benzamides (Sulpiride, Remoxipride, Amisulpride),diazepines/oxazepines/thiazepines (Clozapine, Olanzapine, Quetiapine),Aripiprazole, Risperidone, Paliperidone, Zotepine), includingpharmaceutically acceptable salt and ester forms thereof. Combinationsof two or more of these compounds, or combinations with other compounds.

Particularly preferred would be the use of the current invention in thetreatment of schizophrenia or mania associated with bi-polar disorder aswell as other conditions. The formulation would comprise one or more ofAripiprazole, Clozapine, Zyprasidone, Molindone, Quetiapine, Olanzapine,Risperidone, Paliperidone, Iloperidone, or pharmaceutically acceptablesalts and ester forms thereof, and possibly in combination with otheractive ingredients.

In one embodiment, the formulation comprises a sustained releaseformulation of Risperidone. The amount of formulation delivered could be10 micro-liters to 10 milliliters, preferably 0.25 to 2 milliliters,most preferably about 0.5 milliliter. Dosing frequency could be fromweekly to 4 times yearly, preferably bi-weekly to bi-monthly, mostpreferably monthly. The formulation could be stable for at least 6months, preferably more than 1 year, most preferably 2 years or more.

In a preferred embodiment of the invention for the delivery ofResperidone and other active pharmaceutical ingredients, the depot isdelivered using the needle free injector as described in U.S. Pat. No.6,620,135, U.S. Pat. No. 6,554,818, U.S. Pat. No. 6,415,631, U.S. Pat.No. 6,409,032, U.S. Pat. No. 6,280,410, U.S. Pat. No. 6,258,059, U.S.Pat. No. 6,251,091, U.S. Pat. No. 6,216,493, U.S. Pat. No. 6,179,583,U.S. Pat. No. 6,174,304, U.S. Pat. No. 6,149,625, U.S. Pat. No.6,135,979, U.S. Pat. No. 5,957,886, U.S. Pat. No. 5,891,086, and U.S.Pat. No. 5,480,381, encorporated herein by reference. Although manysustained release and depot formulations could be used with thisinjector for the delivery of Risperidone and other compounds, in apreferred embodiment, the formulation comprises sucrose acetateisobutyrate (SAIB) as described in U.S. Pat. No. 5,747,058.

The current invention describes various viscous formulations that can bedelivered using a needle-free injector including the injector of U.S.Pat. No. 5,891,086 to provide for SC, ID, IM and other types ofdelivery. These formulations include various polymers, carriers, as wellas API's in various physical forms.

An aspect of the invention is a method of injecting an animal,preferably a mammal, most preferably a human patient. The methodincludes loading a liquid formulation into a needle-free injectordevice. This loading can occur at the site of care, but is preferablyperformed at the factory. The formulation is comprised of apharmaceutically acceptable drug in a carrier. The formulation has aviscosity as described herein, which viscosity is preferably about 5 cSor more at about 20° C. When the formulation is loaded into theneedle-free injector about 0.1 ml of formulation or more of theformulation is extruded from the device in a narrow stream through anexit nozzle of the device. The stream is extruded at a rate of speedsuch that the stream punctures the skin of the patient such as a humanpatient. The 0.5 ml of formulation is extruded from the nozzle of thedevice through the skin in about 1 second or less, more preferably lessthan about 0.1 second.

The formulation may include particles such as microparticles and mayinclude an agent which affects the viscosity of the formulation whichmay enhance the viscosity or decrease the viscosity as needed. Suchviscosity enhancing agents are described within U.S. Pat. No. 6,667,061and include compounds such as sodium carboxymethylcellulose. Theformulation may also include wetting agents or other components whichmay generally be found within injectable formulations. The inventionincludes containers which are specifically designed for use inconnection with needle-free injector devices which containers haveloaded therein formulations of the invention which are particularlysuitable for injection in a manner as described here. Some formulationsare designed such that when the formulation is injected the viscosity ofthe formulation increases due to body temperature forming a solid orsemi-solid implant within the patient. Such formulations are usefulparticularly with respect to providing controlled release of the drugcontained within the formulation.

The global pharmaceutical market is growing rapidly. This growth isexpected to continue and probably increase further. The genomics andproteomics revolutions, combined with huge advances in proteindevelopment, monoclonal antibodies and other areas, have meant that themarket for injectable drugs is probably growing faster than most sincethe majority of these molecules are too large and/or fragile to bedelivered by other methods such as orally.

Controlled release (CR) drug delivery systems are used to improve thetherapeutic response by providing blood levels that are moretherapeutically useful, and usually more consistent and stable comparedto immediate release dosage forms. They can result in a reduction inadverse reactions since a) less drug may be required b) the drug may betargeted to the site in vivo avoiding high systemic levels, or c) lowerpeak plasma concentrations are required. As a consequence of targetedand controlled release, patient compliance may be improved due to lowerdosing frequencies and simpler dosing regimens. With targeting and morecontrolled, sustained, predictable levels, efficacy may also beenhanced. CR parenteral drug delivery systems include but are notlimited to: suspensions, liposomes, microspheres, gels, polymers, andimplants. Tiny microspheres and larger implantable devices can be usedto modify release over periods of months to years. These deliverysystems are becoming increasingly utilized by the pharmaceuticalindustry to deliver drugs for treatment or prevention of a variety ofdiseases.

Furthermore, many pharmaceutical companies have developed or aredeveloping sustained release formulations, to give a betterpharmacological effect and/or a decreased frequency of injection.

However, it is difficult to formulate many of these molecules intostable solutions that are sufficiently concentrated to inject areasonable sized dose (<1 ml). These formulations are also usuallyhighly viscous—some are even gel-like with a viscosity of many Poise.This means that they are impractical to inject using a conventionalneedle and syringe.

Viscosity Versus Injection Time

A laboratory trial was performed to understand the difficulties ofinjecting viscous liquids using a needle and syringe and to determinewhether the theory is applicable. Viscous fluids were forced through theneedle using a hand-powered syringe and the injection time was recordedfor a given applied force. Experimental details and results aredescribed in detail in the example section.

Results from this study indicated that needle-free injectors with anozzle that has a substantially larger orifice/length ratio as comparedto a conventional needle, and are capable of delivering formulations ata high driving pressure, have the potential to deliver liquids that arethousands of times more viscous than those that can be delivered using aneedle and syringe.

Improved Drug Release Profile for Surface Eroding Formulations

When injected with a needle and syringe, most depots will form asubstantially spherical depot. In contrast, a needle-free injector canform a more spread out, complex form with a larger surface-to-volumeratio than a sphere. A spherical depot is less preferred for surfaceeroding systems, because as the depot erodes, the surface area decreasesas the volume decreases. A preferred shape would be a sheet, orsheet-like shape. This type of shape would not substantially decrease insurface area as the depot erodes. Therefore, needle free injectors havethe capability of actually improving the drug release kinetics of adepot, resulting in a more constant rate of drug release.

Examples of surface eroding systems include polymer families ofpolyanhydrides and poly(ortho esters) In 1985, Langer et. Al. developedthe polyanhydride poly[bis(p-carboxyphenoxy)]propanesebacic acid(P(CPP:SA)), an extremely hydrophobic polymer with surface-controllederosion. The polifeprosan 20 with carmustine implant (Gliadel® wafer)entered the U.S. market in 1996, and is today approved in severalcountries of the world. Studies have been reported where poly orthoesters were used for small molecule as well as macromoleculeapplications (Heller et al. European Journal of Pharmaceutics andBiopharmaceutics 50 (2000) 121±128, U.S. Pat. No. 6,667,371).

Pain During Injection

Pain and discomfort at the injection site may result in patients'refusal of depot injections. (J Clin Psychiatry. 2001 November;62(11):855-9) The authors reported a study where long-acting depotinjections of antipsychotic medications for patients suffering fromschizophrenia were evaluated for pain. The depot injections caused pain,which was maximal immediately after the injection. A correlation existedbetween reported injection site pain and the effect it had on patients'attitude toward the depot injection as reported by the patients.

As per the package insert for Nutropin Depot, in studies involving 138pediatric patients treated with Nutropin Depot, the most frequentadverse reactions were injection-site reactions, which occurred innearly all patients. On average, 2 to 3 injection-site adverse reactionswere reported per injection. These reactions included nodules (61% ofinjections), erythema (53%), pain post-injection (47%), pain duringinjection (43%), bruising (20%), itching (13%), lipoatrophy (13%), andswelling or puffiness (8%). The intensity of these reactions wasgenerally rated mild to moderate, with pain during injectionoccasionally rated as severe (7%). Cooper et al. reported (Anaesthesia,Volume 55 Issue 3 Page 247, March 2000) significantly less pain oninjection with the needle-free injector than with the 25 G needle.

In a study that included comparing pain for needle-free and needle andsyringe delivery, using a visual analogue scale, 60% of subjectsreported no injection pain with the needle-free injector as compared to30% of subjects with the needle and syringe. 41% of subjects reportedpain levels of 4 or less, whereas 65% of subjects reported this degreeof pain with needle and syringe (stout et al, Drug Delivery Technology,April 2004, Vol 4, No.3).

Viscous Controlled Release Formulations

A number of specific compounds as well as generic descriptions ofcompounds which may be used in needle-free injector formulations aredisclosed here. Further, numerous patents and publications which areincorporated herein by reference are disclosed for teaching otherformulations which could be used in connection with the invention.However, it is important to note that the invention is directed towardshigh viscosity formulations and such high viscosity formulations are, ingeneral, formulations which behave in a manner such as that shown withinFIG. 3. Specifically, the formulation will have a viscosity at about 20°C. such that the viscosity is in a range of 1 to about 10,000 cS and canbe delivered by needle-free injector device in about 1 second or less.Examples of specific formulations include those which have a viscosityin the range of 100 to about 10,000 cS at about 20° C. and those whichcan be delivered (0.5 ml) by a needle-free injector device in about 0.1second or less. In general, when such formulations are administered byhypodermic needle injection, the injection requires about 10 seconds ormore. Accordingly, the formulations and compounds described below shouldbe reviewed and considered by those skilled in the art withconsideration to obtaining the desired viscosity levels such that theformulation (0.5 ml) could be delivered using a needle-free injectordevice in about 0.1 second and could not be readily delivered by ahypodermic needle injecting device in such a short period of time ormore specifically, those formulations wherein the hypodermic needleinjector device requires more than 1 second, more than 2 seconds, morethan 3 seconds, or more than 10 seconds to complete the injection.

An example of a sustained release polymer formulation that can bedelivered by needle-free injection could use poly(ortho esters) as thevehicle. For example, see U.S. Pat. Nos. 4,304,767, 4,957,998, 5,968,543and WO 02/092661 as well as Adv. Polymer Sci., 107, 41-92 (1993) andreferences therein. Viscosities of these controlled release polymerswere reported to be in the 1,500 cP range (see Biomaterials, 23, 2002,4397-4404). Considerably higher forces were required for highermolecular weight polymers (see Adv. Drug Del Reviews, 53, 2001, 45-73).

The invention may be used wherein the pharmaceutical agent is selectedfrom a group consisting of antibodies or monoclonal antibodies,anti-inflammatory agents, antibacterial agents, antiparasitic agents,antifungal agents, antiviral agents, anti-neoplastic agents, analgesicagents, anaesthetics, vaccines, central nervous system agents, growthfactors, hormones, antihistamines, osteoinductive agents, cardiovascularagents, anti-ulcer agents, bronchodilators, vasodilators, birth controlagents and fertility enhancing agents, interferon alpha, osteoporosisdrugs including PTII and PTII analogs and fragments, obesity drugs,psychiatric drugs, anti-diabetes, female infertility, AIDS, treatment ofgrowth retardation in children, hepatitis, multiple sclerosis, migraineheadaches, and allergic reactions.

The invention may be used wherein the pharmaceutical agent is apolypeptide or protein member selected from the group consisting ofoxytocin, vasopressin, adrenocorticotropic hormone, epidermal growthfactor, platelet-derived growth factor (PDGF), prolactin, luliberin,luteinizing hormone releasing hormone (LHRH), LHRH agonists, LHRHantagonists, growth hormone (human, porcine, bovine, etc.), growthhormone releasing factor, insulin, erythropoietin, somatostatin,glucagon, interleukin-2 (IL-2), interferon- .alpha., .beta., or .gamma.,gastrin, tetragastrin, pentagastrin, urogastrone, secretin, calcitonin,enkephalins, endorphins, angiotensins, thyrotropin releasing hormone(TRH), tumor necrosis factor (TNF), nerve growth factor (NGF),granulocyte-colony stimulating factor (G-CSF), granulocytemacrophage-colony stimulating factor (GM-CSF), macrophage-colonystimulating factor (M-CSF), heparinase, bone morphogenic protein (BMP),hANP, glucagon-like peptide (GLP-1), interleukin-11 (IL-11), renin,bradykinin, bacitracins, polymyxins, colistins, tyrocidine, gramicidins,cyclosporins and synthetic analogues, modifications andpharmacologically active fragments thereof, enzymes, cytokines,antibodies, vaccines and polymers, which may be copolymers or conjugatescomprised of poly(ortho esters).

Formulations of the invention may include a polymer selected from thegroup consisting of but not limited to poly-lactic acid, poly glycolicacid, copolymers of lactic acid and glycolic acid and mixtures thereofor the formulation includes

-   -   Formulations of the invention may include a polymeric material        selected from the group consisting of but not limited to        copolymers of lactic acid and glycolic acid, and mixtures        thereof.

In one embodiment of the invention the formulation is capable of forminga depot. In one embodiment of the invention the formulation is in apolymeric, copolymeric or conjugated form using peptides or otherconjugates wherein the polymers, copolymers or conjugates are comprisedof methacralate or wherein said polymers, copolymers or conjugates arecomprised of caprolactone or wherein said polymers, copolymers orconjugates are comprised of chitosan or wherein said polymers,copolymers or conjugates are comprised of polyanhydrides or wherein saidpolymers, copolymers or conjugates are comprised of polyethylene glycolor wherein said polymers or copolymers are comprised ofpolyphosphoesters or wherein said polymers, copolymers or conjugates arecomprised of polyphosphosphazenes or wherein said polymers, copolymersor conjugates are comprised of dextran or other carbohydrates or sugarsor wherein said polymers, copolymers or conjugates are comprised ofdendrimers or other star polymers such as fullerenes or wherein saidpolymers, copolymers or conjugates are in a colloidal or suspension formor wherein said polymers, copolymers or conjugates are in a cross-linkedform or present as crystals or nanocrystals or wherein said polymers,copolymers or conjugates are calcium phosphate particles ornanoparticles or wherein said polymers, copolymers or conjugates arecomprised of polyetherester or wherein said polymers, copolymers orconjugates are comprised of hyaluronic acid or wherein said polymers,copolymers or conjugates are comprised of collagen or wherein saidpolymers, copolymers or conjugates are comprised of gelatin or whereinsaid polymers, copolymers or conjugates are comprised of dextran orwherein said polymers, copolymers or conjugates are comprised ofamphiphiles or wherein said polymers, copolymers or conjugates arecomprised of lipids and various physical agglomorates of lipids with orwithout polymer hybrids including but not limited to liposomes,hexagonal shapes or wherein said polymers, copolymers or conjugates arecomprised of methacrylamides or wherein said polymers, copolymers orconjugates are comprised of polyethylene oxides or wherein saidpolymers, copolymers or conjugates are comprised of emulsifiable lipidsor wherein the non-polymeric non-water soluble liquid carrier materialis sucrose acetate isobutyrate or wherein said polymers, copolymers orconjugates are comprised of calcium phosphate or wherein it is comprisedof but not limited to a polymeric, encapsulated, dispersed, suspendedsugar or carbohydrate constituents or wherein the formulation is in anoil suspension or the formulation is in the form of liquid crystals.

Liposomes

Phospholipid vehicles as drug delivery systems were proposed as“liposomes” in 1965 by Bangham [Bangham et al., J. Mol. Biol. 13 (1)(1965) 238-252.]. In the early 90's, three products for intravenousinjection entered the market: a liposomal preparation of amphotericin B(Ambisome®) for systemic fungal treatment, and two chemotherapeuticliposomal formulations: liposomal Doxirubicin (Doxil®) and liposomalDaunorubicin (Daunosome®).

Pegylated liposomes have been shown to have long circulating halflives.Vasopressin entrapped in PEGylated long-circulating liposomes remainbioactive one month after intravenous injection.

A new approach, rather than using unilamellar or multilamellarliposomes, is based on microscopic, spherical particles composed ofhundreds of non-concentric aqueous chambers encapsulating the drug to bedelivered. (DepoFoam™ system). These multivesicular liposomes (1-100 μm)contain multiple non-concentric internal aqueous compartments and leadto an increase in the encapsulation efficiency. After subcutaneousinjection, the release of encapsulated peptide and protein was shown tobe prolonged up to 7 days for Insulin and up to 3 weeks for theLeuprolide formulation [Ye, Q et al., DepoFoam technology, J. Control.Rel. 64 (1-3) (2000), 155-166.].

The company Novosom AG has patented a novel liposome-based depot systemfor proteins and peptides (Cagicles®). These depots are produced by atwo step method: first, proteins are dissolved in an aqueous medium andthen added to solutions of membrane-forming substances, which areselected such that the resulting membrane enters into a reversiblemutual reaction with the protein. This mild-condition process enables toincrease the encapsulation rate over 30% of incorporated protein.Furthermore, a one month sustained protein release was feasible aftersubcutaneous or intramuscular injection of the Cagicles depots [Panzner,S., Novosom AG, Application No. 2000-EP11079, Patent No. WO 2001034115(2000)]. These studies have proven the basic applicability of liposomes.The solubility benefits of liposomes are well known and reported.

Lipid Nanoparticles and Microspheres

Solid lipid nanoparticles (SLNs) represent a colloidal carrier systemmainly based on triglycerides. Due to their hydrophobic nature and theirsmall size, SLNs may be more appropriate for incorporation of lipophilicdrugs, which can be easily dissolved in the melted mixture. Forinstance, only small quantities of lysozyme can be incorporated intovarious lipids (Almeida et al, Int. J. Pharm. 149 (2) (1997) 255-265).Solid lipid nanoparticles own potential for the encapsulation of drugswith a low solubility (e.g. paclitaxel), for the application ofsurface-modified SLNs in drug targeting, or maybe for the use asadjuvant for vaccines. Furthermore, it can be hypothesised that SLNs canbe applied for oral drug delivery in the form of aqueous dispersions orthat they can alternatively be used as additives in traditional dosageforms such as tablets, capsules or pellets.

U.S. Pat. No. 6,277,413 describes a biodegradable microsphere having amatrix, the matrix comprising at least one type of biodegradablepolymer, and at least one type of lipid; and a physiologically activesubstance which is releasable from the biodegradable microsphere.

Lipid Crystals

EP 0767,656B1 describes a pharmaceutical composition, which isglycerol-ester based and contains diacyl glycerol as well asphospholipid(s), or a polar group containing water, glycerol, ethyleneglycol or propylene glycol. The proportions between the components areadjusted to form an L2 phase or a liquid crystalline phase, with thebiological material being dispersed or dissolved in the L2 or liquidcrystalline phase.

Oil Suspensions

Generally, the viscosity of oily media is considerably higher than theviscosity of an aqueous phase such as buffer. Therefore, drug releasecan be prolonged by implementing oil suspensions. In addition, theviscosity of the oily carrier can be further increased by the additionof gelling agents such as aluminium monostearate—thus enabling thecontrol of process parameters like drug solubility and drug transferrate. A further important aspect using oils as drug carrier refers tothe distribution coefficient of compounds in the oily medium and thesurrounding tissue. A lipophilic drug with a high distributioncoefficient will primarily accumulate in the oily medium resulting infurther deceleration of effective drug actions.

For several years, various peptides and proteins have been dispersed inoils to engineer sustained-release formulations. Nestor et al. patentedas early as 1979 the development of long-acting injectable depotformulations for super-agonist analogues of luteinizinghormone-releasing hormone (LH-RH), applying oils such as peanut oil orsesame oil and a gelling agent such as aluminium stearate [Nestor et al,Syntex Inc., U.S. Pat. No. 4,256,737 (1979).].

Hydrogels

Thermoreversible hydrogels are of great interest in drug delivery. Theseinclude thermosensitive gel materials including poly(ethyleneglycol)/poly(propylene glycol) block copolymers (poloxamers),poly(ethylene glycol)/poly(butylenes glycol) block copolymers,poloxamer-g-poly(acrylic acid) and copolymers of Nisopropylacrylamidethat exhibit a sol-to-gel transition in aqueous solutions. Diblockcopolymers of poly(ethylene oxide) (PEG) and poly(lactic acid) (PLA),and triblock copolymers of PEG-PLGA-PEG are also used as alternativehydrogels that would provide biodegradable and injectable drug-deliverysystems under physiological conditions. Some natural polymers includinggelatin, agarose, amylase, amylopectin, cellulose derivatives,carrageenans, and gellan, exhibit thermoreversible gelation behavior.Some cellulose derivatives of natural polymers, such as methyl celluloseand hydroxypropyl cellulose, exhibit reverse thermogelation behavior(gelation at elevated temperatures). Viscosity of these hydrogels is aconcern for parenteral delivery. Viscosity of these hydrogels can beextremely high at low shear rates (Eur. J. of Pharm. and Biopharm., 59,2005, 333-342). Poly hydroxyl methacralate is extensively used inhydrogel formulations (Peppas et al., European Journal of Pharmaceuticsand Biopharmaceutics 50, 2000, 27). U.S. Pat. No. 6,602,952 describes apolymeric structure comprising a multifunctional poly(alkylene oxide),such as a poly(ethylene glycol) derivative, covalently cross-linked to apolymer selected from the group consisting of chitosan and conjugates ofchitosan and a monofunctional poly(alkylene oxide), such as methoxypoly(ethylene glycol). In aqueous media, the polymeric structure forms ahydrogel.

Depot Formulations and Implantables

Implantable drug delivery devices provide an attractive therapeutic toolfor treatment of a variety of diseases and conditions, especially when asustained release effect is also added to the therapy. Variousimplantable drug delivery devices have been developed, and are basedupon different mechanisms to accomplish movement of drug from areservoir to the treatment site. U.S. Pat. No. 4,938,763 discloses amethod for forming an implant in situ by dissolving a non-reactive,water insoluble thermoplastic polymer in a biocompatible, water solublesolvent to form a liquid, placing the liquid within the body, andallowing the solvent to dissipate to produce a solid implant. U.S. Pat.No. 5,747,058 describes a composition for the controlled release ofsubstances that includes a non-polymeric non-water solublehigh-viscosity liquid carrier material of viscosity of at least 5,000 cPat body temperature that does not crystallize neat under ambient orphysiological conditions.

Delivery of Macromolecules

Protein formulations at high concentrations may also have physicalproperties that impact the ability to easily deliver the protein drug.For example, higher viscosity preparations may be difficult toadminister by injection. Syringes for SC injection are often equippedwith 26 or 27 gauge needles (J of Pharmaceutical Sciences, Volume 93,Issue 6, p 1390-1402).

Proteins such as monoclonal antibodies are often administered withfrequent dosing regimens and at high doses (several mg/kg). Twoantibodies, Rituxan1 and Herceptin1 that have been approved for thetreatment of cancer are intravenously administered in hospitals, butseveral programs are underway for use of monoclonal antibodies to treatdiseases that may require outpatient administration, and hence requirethe development of SC route of administration. Treatments with highdoses, e.g., more than 1 mg/kg or 100 mg per dose, require developmentof formulations at concentrations exceeding 100 mg/mL because of thesmall volume (<1.5 mL) that can be given by the SC routes (J ofPharmaceutical Sciences, Volume 93, Issue 6, p 1390-1402).

U.S. Pat. No. 6,541,606 describes protein crystals or crystalformulations that are encapsulated within a matrix comprising apolymeric carrier to form a composition. The formulations andcompositions enhance preservation of the native biologically activetertiary structure of the proteins and create a reservoir which canslowly release active protein where and when it is needed.

Conjugated Systems

Polymer carrier systems may have certain advantages over non-polymericcarriers in terms of avoiding uptake by macrophages. Because liposomesare spherical vesicles made of phospholipids are particles, they gettaken up by macrophages. High levels can be found in the liver andspleen, even when the liposomes are given “stealth” characteristics bycoating them with PEG. Antibodies, meanwhile, have the disadvantage thatmost receptors on tumor cells are also present on normal cells, makingit hard to find ones that are unique to cancer.

In contrast, water-soluble polymers allow working with a single moleculerather than a large particle. To avoid the liver and spleen, unchargedhydrophilic polymers, such as PEG and N-(2-hydroxypropyl)methacrylamidecan be used. When these polymers are hydrated, they can circulate in theblood for periods of up to about 24 hours (C&E News, Volume 80, Number34, 39-47).

Examples of other conjugated systems include PEGylation. PEGylationdecreases the rate of clearance from the bloodstream by increasing theapparent molecular weight of the molecule. Up to a certain size, therate of glomerular filtration of proteins is inversely proportional tothe size of the protein. Decreased clearance can lead to increasedefficiency over the non-PEGylated material (see Conforti et al., Pharm.Research Commun vol. 19, pg. 287, 1987 and Katre et al., Proc. Natl.Acad. Sci. U.S.A. vol. 84, pg. 1487, 1987). The conjugation could beeither in-vitro or in-vivo.

WO2005034909A2 describes a hyperbranched polymer attached to a core anda biologically active moiety. The biologically active moiety is attachedto the core by means of a substantially non-enzymatically cleavablelinker L. The composition can be used to deliver the biologically activemoiety to its target.

U.S. Pat. No. 6,946,134 describes therapeutic proteins fused to albuminor fragments or variants of albumin that exhibit extended shelf-lifeand/or extended or therapeutic activity in solution. The role of albuminas a carrier molecule and its inert nature are desirable properties foruse as a carrier and transporter of polypeptides in vivo. The use ofalbumin as a component of an albumin fusion protein as a carrier forvarious proteins has been suggested in WO 93/15199, WO 93/15200, and EP413 622. The use of N-terminal fragments of HA for fusions topolypeptides has also been proposed (EP 399 666).

U.S. Pat. No. 5,367,051 describes fullerene-functionalizedamine-containing polymers and polymerizable monomers characterized byhigh temperature stability, i.e., capable of withstanding a temperatureof at least about 300.degree. C., when in polymerized form. Thefullerene groups are bonded to the polymers through the amine groups onthe polymer.

WO Patent No. 2005073383 describes novel heterodimeric fusion proteinscomprising a first polypeptide including an alpha subunit of FSH (aFSH)linked directly or indirectly to a binding partner of neonatal Fcreceptor (FcRn) and a second polypeptide including a beta subunit of FSH(βFSH) linked directly or indirectly to an FcRn binding partner. Theconjugated polypeptide has increased half-life and bioavailability ascompared to traditional forms of FSH therapy.

Dendrimers

Dendrimers are well-defined polymeric structures. Dendrimers are basedon repeating hyperbranched structures emanating from a central core(U.S. Pat. No. 4,507,466). Typical dendrimers are based onpolyamidoamine (PAMAM), polyethylene imine (PEI), polypropylene imine orpolylysine. These synthetic macromolecules are assembled in a stepwisefashion, with each reaction cycle adding another layer of branches(dubbed “generation”). Dendrimers are synthetically accessed bystepwise, divergent “bottom-up” or convergent “top-down” synthesis.Central structural component is the core unit from which hyperbrancheddendrimers extend in a radially symmetric fashion. The core may provideat least two reactive groups for dendrimer conjugation, it may also beof heterofunctional nature and protecting groups may be used. In thelatter case, the dendrimer may be assembled, and a guest compound may besubsequently conjugated to an anilin core by means of orthogonalchemistries (WO 88/01180). The core and dendrimers form the interior orbackbone of a dendrimer. As a consquence of the spherical symmetrysupported by sterical crowding, the terminal groups of the hyperbranchesare defining the exterior. In higher generation dendrimers, the terminalbranches form rather dense shells and flexible internal voids have beendiscovered. It is understood, that for a given dendrimer these cavitiesare filled up by backfolded end groups and tightly coordinated solventmolecules. Dendrimers are related to micelles, similary well suited tocomplex hydrophobic compounds. But in contrast they exhibit higherstructural order because of their monomolecular nature and the absenceof a dynamic equilibrium of various species. Synthetic compounds canonly diffuse into dendrimers if certain structural requirement such asconformational rigidity and flatness as well as charge distribution suchas affinity to tertiary amines are met. Various apolar compounds such aspyrene or naphthalene have been encapsulated in dendrimers.

In U.S. Pat. No. 5,714,166 and WO 95/24221, dendrimer-protein conjugatesare revealed. PAMAM dendrimers of G4 are covalently coupled throughtheir terminal functional groups to insulin, fluorescently labeledinsulin, avidin, monoclonal antibodies and bradykinin. The reactivegroups used for conjugation are only present at the surface of thedendrimers, and therefore any covalent adduct generated by the leachedmethod will be associated with the dendrimer exterior.

PAMAM dendrimers contain free amine groups on their surfaces and readilyassociate with DNA through electrostatic interactions.

WO 01/07469 details water-soluble polypeptide dendrimers constituted ofornithin and glycine amino acids. The patent application also teachesthe non-covalent encapsulation of an oligosaccharide, heparin, bydendrimerization of the dendrimer core in presence of heparin under mildconditions. The oligosaccharide is released from the dendrimer bylight-induced cleavage of W-labile bonds within the dendritic backbone.The core structure used here was tris(2-maleimidoethyl)amine.

Other Polymeric Systems

Passirani et al. evaluated the use of heparin, dextran and methylmethacralate in a biomimetric approach in the development of drugcarriers escaping early capture by phagocytosis (Passirani et al, PharmRes, 1998, 15, 1046).

The synthesis of hybrid block and graft copolymers of polyphosphazenesand polystyrene is a way to combine the attributes of both polymers andgenerate new properties. Many of the valuable properties of therespective phosphazene and styrene homopolymers can be combined withoutsacrificing the overall solid state or solution properties of bothpolystyrene and polyphosphazene polymers. U.S. Pat. No. 6,392,008describes such compositions of polyphosphazene-containing polymers.

U.S. Pat. No. 5,176,907 describes biocompatible and biodegradablepoly(phosphoester-urethanes), compositions comprising thepoly(phosphoester-urethanes), and methods of use as a drug deliverydevice and an implant.

Needle-Free Injectors

Specific injector devices which might be used with the present inventioninclude, but are not limited to, injectors chosen from IntraJect®,Biojector 2000, Iject®, Intelliject, Injex, HSI 500, Medijector vision,Mini-Ject, PenJet®, Vitajet, PMED, Avant Guardian 101, Activa, Antares,Ypsomed, Medjet, The Medical house, Am-O-Jet™, Crossject™, DermoJet® &Vacci-Jet, Hyjettor™, IM-O-JET™, and an LectraJet™.

Needle-free injection of medications and vaccines represents analternative route of administration that is as effective as needle andsyringe but free of many of the problems. This method of injectionutilizes a fine stream of medication at high pressure to penetrate theskin. The absence of hypodermic needles from the injection processremoves the potential for needle-stick injuries and simplifies disposal,as well as removing a significant visual trigger for needle-phobia. Therapidity of needle-free injections (typically 0.5 second or less)further enhances patient compliance and acceptance.

Different needle-free injection devices in current use can bedistinguished by the source of the power for injections—for example aspring, compressed gas, or a chemical reaction. Each of these designshas particular advantages and disadvantages.

Spring-powered devices have the advantage of being relativelyinexpensive and durable. The disadvantages of this type of injectorresult from the limited amount of force that is generated by a coiledspring, which to some extent reduces the versatility of this class ofinjector.

Examples of spring-powered, needle-free injection devices include theActiva AdvantaJet, which is designed primarily for subcutaneousinjection of 0.5-50 units of insulin. The Equidyne Injex is directedprimarily at the diabetes market, and can deliver 0.02-0.5 ml of insulinsubcutaneously. Use of the Injex for delivering vaccines is beingexplored as well (Sarno M J et al, 2000. Pediatr. Infect. Dis. J.19:839-842). The Bioject/Vitajet 3 was originally developed forsubcutaneous injection of insulin, and has recently been adapted bySerono as a delivery platform for their Saizen (Silverstein et al, 2001Endocrine 15:15-17) and Serostim (Murray et al, 2001, Today'sTherapeutic Trends 19:137-155) formulations of recombinant human growthhormone. Needle-free delivery of growth hormone has considerable appealfrom the perspective of acceptance and compliance in the paediatricmarket (Saizen) and improved safety for injecting HIV-positive patients(Serostim).

The Antares/Medi-Jector VISION is a spring-powered device intended forsubcutaneous injections of 2 to 50 units of insulin (Bremseth et al,2001, Diabetes Technol. Ther. 3:225-232). Medi-Ject devices have alsoproven to be effective in delivering other medications (Verrips et al,1998, Acta Paediatr. 87(2):154-8) and DNA vaccines (Anwer et al., 1999,Pharm. Research 16:889-895). The Medi-Jector VISION uses a replaceabletransparent needle- free syringe, which is available in three orificesizes. Changing the orifice size modulates the injection pressure toaccommodate differences in the thickness and penetrability of variousskin types and anatomical locations. Other similar Medi-Jector devicesare marketed for administering recombinant human growth hormone (GH,Hirasing et al., 1998Acta Paediatr. 87(2):154-8).

Gas-powered devices present the advantages of the more sustained forceprovided by compressed gas relative to a coiled spring. Thus, largervolumes of injection (up to 1.0 ml) can be administered via either thesubcutaneous or intramuscular route. The primary disadvantage ofgas-powered devices is that, unlike a spring, the source of power isexhaustible and must therefore be replaced periodically.

Examples of gas-powered injection devices include the CO2-poweredBiojector 2000, the advantages of which include versatility, as it canprovide IM and SQ injections of volumes ranging from 0.1 to 1.0 ml(Stout R, Miller R, 1997). Visionary Medical Products manufactures thePenJet, a small disposable injector that uses pre-filled ampoules todeliver up to 0.5 ml of medication. Activation of the device ispressure-sensitive, which ensures that the user applies the appropriateamount of force when administering an injection. To provide increasedconvenience, National Medical Products has developed the J-Tip, aCO2-powered disposable injector designed to deliver subcutaneousinjections of 0.02 to 0.25 ml of insulin. Injection of lidocaine and lowmolecular weight heparin with the J-Tip has been evaluated as well(Hollingsworth S J et al., 2000. Ann. R. Coo. Surg. Eng. 82:428-431).

U.S. Pat. No. 5,911,703describes a two-stage jet injector of the presentinvention includes, in combination, a syringe unit, a drive mechanismfor advancing the syringe plunger in a two-stage sequence, and a suctioncompartment which surrounds an injection tube of the syringe. The drivemechanism includes a push rod which is positioned longitudinallyco-linear with the plunger of the syringe, when the syringe unit isoperably connected to the drive mechanism. Accordingly, advancement ofthe plunger into the syringe chamber is caused by movement of the pushrod. In accordance with the present invention, the push rod is driven bytwo separate springs, which are engaged with the push rod, and which arecoaxially positioned around the push rod. Specifically, the first of thetwo coaxial springs is an impulse spring which is characterized by arelatively high spring constant and the fact that it is dimensioned tohave a relatively short action distance. In comparison with the firstspring, the second spring, a perfusion spring, has a lower springconstant and a longer action distance.

EXAMPLES

The following examples are put forth so as to provide those of ordinaryskill in the art with a complete disclosure and description of how tomake and use the present invention, and are not intended to limit thescope of what the inventors regard as their invention nor are theyintended to represent that the experiments below are all or the onlyexperiments performed. Efforts have been made to ensure accuracy withrespect to numbers used (e.g. amounts, temperature, etc.) but someexperimental errors and deviations should be accounted for. Unlessindicated otherwise, parts are parts by weight, molecular weight isweight average molecular weight, temperature is in degrees Centigrade,and pressure is at or near atmospheric.

Example 1 Viscosity Versus Injection Time

Two trials were undertaken to determine the injection time of viscousfluids with both Intraject and a needle and syringe. The viscous fluidsused in the trials were a range of different viscosity Dow Comingsilicone oils. For the needle and syringe a range of the fluids wereejected by hand and the times recorded, for Intraject an instrumentedforce sensor was used to measure injection time for all availableviscosities, however high-speed video was used for the thickest of thefluids because they did not flow properly off the force sensor and sodid not give useable readings.

For the needle trial a 3 ml syringe and a 23 G needle were used; theneedle had an internal diameter of 0.38 mm and was the closest availableneedle size to that of the Intraject orifice (0.3 mm) The needle had alength of 31 mm and the syringe had an internal cross-sectional area of58.5 mm². Liquid formulation in an amount of 0.5 ml with viscosities of50, 100, 500 and 1,000 cS were ejected from the needle and syringe byhand and the times taken were recorded and averaged. As much force aspossible was applied by hand to the syringe and a similar force wasapplied to all the oils used. However, with the thinner fluids it washard to apply as large a force as with the thicker ones because thesyringe plunger was moving faster. When a similar force was applied to aload cell about 15N was recorded.

An Intraject needle-free device was used which included a standard Ø0.3mm orifice. The same orifice was used for all the firings to remove anyvariations that may arise from differences between orifi. Liquidformulations in an amount of 0.5 ml with viscosities of 1, 5, 10, 20,50, 100, 500 and 1,000 cS were used in each device. To determine theinjection time of both the 12,500 cS and 30,000 cS fluids high-speedvideo was used.

Both sets of injection time data have been plotted together in FIG. 3.However, because of the large differences in injection times for aneedle and Intraject the only way to see both lines clearly is to plotthe graph using logarithmic scales for both axes. Using the theory forfully developed flow and a force of 15N the theoretical time to inject0.5 ml of the viscous liquids was calculated and also plotted.

The key results were (see FIGS. 2 and 3):

A 23G needle, 31 mm long, would take 90 seconds to inject 0.5 ml of a1,000 cS solution with the user applying as much force as possible withtheir thumb on the end of the syringe (approx 15N). This compares toless than a second for a drug with the viscosity of water.

By contrast, Intraject took 0.085 seconds to deliver a 1,000 cSsolution.

The injection time for highly viscous fluids can be extrapolated fromtrial data. For Intraject this gave a 1 second delivery time with 0.5 mlof 150,000 cS fluid and 7 seconds for a 1,000,000 cS fluid. Using a 23 Gneedle and syringe with these fluids would give injection times of 5 hrand 33 hr respectively.

There are two reasons for the difference in performance. Firstly anIntraject nozzle is considerably shorter than the needle, which meansthat viscous flow does not have a chance to develop. Secondly, thedriving pressure in Intraject is much greater than in a needle andsyringe, this leads to a faster flow of liquid and a shorter injectiontime.

The application of fully developed laminar pipe flow theory allows us topredict the injection times for different combinations of needle lengthsand diameters, as well as understand the limits of Intraject with highlyviscous fluids.

Results from this study indicate that needle-free injectors with anozzle that has a substantially larger orifice/length ratio than aneedle, and/or capable of delivering formulations at a high drivingpressure, have the potential to deliver liquids that are thousands oftimes more viscous than those that can be delivered using a needle andsyringe.

While the present invention has been described with reference to thespecific embodiments thereof, it should be understood by those skilledin the art that various changes may be made and equivalents may besubstituted without departing from the true spirit and scope of theinvention. In addition, many modifications may be made to adapt aparticular situation, material, composition of matter, process, processstep or steps, to the objective, spirit and scope of the presentinvention. All such modifications are intended to be within the scope ofthe claims appended hereto.

1.-23. (canceled)
 24. A needle free injector device, comprising: acontainer; a liquid formulation in the container, the formulation havinga viscosity of 5 cS or more at 20° C.; and a nozzle leading from thecontainer, the nozzle comprising a channel and an exit openingconfigured to have a ratio of channel length to exit opening diameter ofless than
 10. 25. The injector of claim 24, wherein the ratio of channellength to exit opening diameter is less than
 7. 26. The injector ofclaim 24, wherein the viscosity of the liquid is more than 10 cS at 20°C.
 27. The injector of claim 24, wherein the viscosity of the liquid is20 cS or more at 20° C. and the ratio of channel length to exit openingdiameter is less than
 5. 28. The injector of claim 24, wherein theviscosity of the formulation is 100 cS or more at 20° C.
 29. Theinjector of claim 24, wherein the ratio of length to exit diameter is1.7±20%.
 30. The injector of claim 24, wherein the viscosity of theformulation is 1000 cS or more at 20° C.
 31. The injector of claim 26,wherein the formulation comprises a pharmaceutically acceptable carrierand a pharmaceutically active drug.
 32. The needle free injector ofclaim 31, wherein the drug is a psychiatric drug.
 33. The injector ofclaim 32, wherein the psychiatric drug is selected from the groupconsisting of chlorpromazine, fluphenazine, mesoridazine, perphenazine,prochlorperazine, promazine, thioridazine/sulforidazine,trifluoperazine, indoles, butyrophenones, thioxanthenes,diphenylbutylpiperidines, loxapine, butyrophenones, indoles, benzamides,diazepines, oxazepines, thiazepines, aripiprazole, risperidone,paliperidone, zotepine, iloperidone, pharmaceutically acceptable saltand ester forms thereof, and combinations of two or more of thesecompounds.
 34. The injector of claim 32, wherein the psychiatric drug isselected from the group consisting of molindone, azaperone, benperidol,droperidol, haloperidol, flupentixol, chlorprothixene, thiothixene,zuclopenthixol, fluspirilene, penfluridol, pimozide, loxapine,melperone, sertindole, ziprasidone, sulpiride, remoxipride, amisulpride,clozapine, olanzapine, quetiapine, and pharmaceutically acceptable saltsand ester forms, and combinations thereof.
 35. The injector of claim 32,wherein the psychiatric drug comprises risperidone.
 36. The injector ofclaim 26, wherein the formulation is a viscous controlled releaseformulation.
 37. The injector of claim 35, wherein the formulationcomprises sucrose acetate isobutyrate.
 38. The injector of claim 31,wherein the pharmaceutically active drug comprises a protein.
 39. Theinjector of claim 38, wherein the protein is selected from the groupconsisting of oxytocin, vasopressin,adrenocorticotropic hormone,epidermal growth factor, platelet-derived growth factor (PDGF),prolactin, luliberin, luteinizing hormone releasing hormone (LHRH), LHRHagonists, LHRH antagonists, growth hormone (human, porcine, bovine,etc.), growth hormone releasing factor, insulin, erythropoietin,somatostatin, glucagon, interleukin-2 (IL-2), interferon-.alpha.,.beta., or .gamma., gastrin, tetragastrin, pentagastrin, urogastrone,secretin, calcitonin, enkephalins, endorphins, angiotensins, thyrotropinreleasing hormone (TRH), tumor necrosis factor (TNF), nerve growthfactor (NGF), granulocyte-colony stimulating factor (G-CSF), granulocytemacrophage-colony stimulating factor (GM-CSF), macrophage-colonystimulating factor (M-CSF), heparinase, bone morphogenic protein (BMP),hANP, glucagon-like peptide (GLP-1), interleukin-11 (IL-11), renin,bradykinin, bacitracins, polymyxins, colistins, tyrocidine, gramicidins,cyclosporins and synthetic analogues, modifications andpharmacologically active fragments thereof, enzymes, cytokines,antibodies, vaccines and polymers, which may be copolymers or conjugatescomprised of poly(ortho esters).
 40. A needle free injector device,comprising: a container; a liquid formulation in the container, theformulation having a viscosity of 5 cS or more at 20° C.; a nozzleleading from the container, the nozzle comprising a channel and an exitopening configured to have a ratio of channel length to exit openingdiameter of less than 10; and a power source for forcing formulationthrough the channel and out of the exit opening at a rate of 500microliters or more per second.
 41. The injector of claim 40, whereinthe ratio of channel length to exit opening diameter is less than 7 andthe power source forces the formulation out of the exit opening at arate of 5,000 microliters or more per second.
 42. The injector of claim40, wherein the viscosity of the liquid is more than 10 cS at 20° C. 43.The injector of claim 40, wherein the viscosity of the liquid is 20 cSor more at 20° C. and the ratio of channel length to exit openingdiameter is less than
 5. 44. The injector of claim 40, wherein theviscosity of the formulation is 100 cS or more at 20° C.
 45. Theinjector of claim 40, wherein the ratio of length to exit diameter is1.7±20%.
 46. The injector of claim 40, wherein the viscosity of theformulation is 1000 cS or more at 20° C.
 47. The injector of claim 42,wherein the formulation comprises a pharmaceutically acceptable carrierand a pharmaceutically active drug.
 48. The injector of claim 47,wherein the drug is a psychiatric drug.
 49. The injector of claim 48,wherein the psychiatric drug is selected from the group consisting ofchlorpromazine, fluphenazine, mesoridazine, perphenazine,prochlorperazine, promazine, thioridazine/sulforidazine,trifluoperazine, indoles, butyrophenones, thioxanthenes,diphenylbutylpiperidines, loxapine, butyrophenones, indoles, benzamides,diazepines, oxazepines, thiazepines, aripiprazole, risperidone,paliperidone, zotepine, iloperidone, pharmaceutically acceptable saltand ester forms thereof, and combinations of two or more of thesecompounds.
 50. The injector of claim 48, wherein the psychiatric drug isselected from the group consisting of molindone, azaperone, benperidol,droperidol, haloperidol, flupentixol, chlorprothixene, thiothixene,zuclopenthixol, fluspirilene, penfluridol, pimozide, loxapine,melperone, sertindole, ziprasidone, sulpiride, remoxipride, amisulpride,clozapine, olanzapine, quetiapine, and pharmaceutically acceptable saltsand ester forms, and combinations thereof.
 51. The injector of claim 48,wherein the psychiatric drug comprises risperidone.
 52. The injector ofclaim 42, wherein the formulation is a viscous controlled releaseformulation.
 53. The injector of claim 51, wherein the formulationcomprises sucrose acetate isobutyrate.
 54. The injector of claim 47,wherein the pharmaceutically active drug comprises a protein.
 55. Theinjector of claim 54, wherein the protein is selected from the groupconsisting of oxytocin, vasopressin,adrenocorticotropic hormone,epidermal growth factor, platelet-derived growth factor (PDGF),prolactin, luliberin, luteinizing hormone releasing hormone (LHRH), LHRHagonists, LHRH antagonists, growth hormone (human, porcine, bovine,etc.), growth hormone releasing factor, insulin, erythropoietin,somatostatin, glucagon, interleukin-2 (IL-2), interferon-.alpha.,.beta., or .gamma., gastrin, tetragastrin, pentagastrin, urogastrone,secretin, calcitonin, enkephalins, endorphins, angiotensins, thyrotropinreleasing hormone (TRH), tumor necrosis factor (TNF), nerve growthfactor (NGF), granulocyte-colony stimulating factor (G-CSF), granulocytemacrophage-colony stimulating factor (GM-CSF), macrophage-colonystimulating factor (M-CSF), heparinase, bone morphogenic protein (BMP),hANP, glucagon-like peptide (GLP-1), interleukin-11 (IL-11), renin,bradykinin, bacitracins, polymyxins, colistins, tyrocidine, gramicidins,cyclosporins and synthetic analogues, modifications andpharmacologically active fragments thereof, enzymes, cytokines,antibodies, vaccines and polymers, which may be copolymers or conjugatescomprised of poly(ortho esters).
 56. A needle-free injector device,comprising: a container; a liquid formulation comprising risperidone andsucrose acetate isobutyrate and a viscosity greater than 10 cS at 20°C.; a nozzle leading from the container, the nozzle having channellength and exit opening configured to have a ratio of channel length toexit opening diameter of less than 10; and a power source for forcingformulation through the channel and exit opening at a rate of 500microliters or more per second.
 57. The injector of claim 56, whereinthe formulation viscosity is greater than 20 cS at 20° C. and the powersource forces the formulation through the channel and exit opening at arate of 5,000 microliters or more per second and the channel length toexit opening diameter is less than 5.